3′,5′-cyclic phosphate prodrugs for HCV infection

• US 9,296,778 B2
• Filed: 05/21/2013
• Issued: 03/29/2016
• Est. Priority Date: 05/22/2012
• Status: Active Grant

• Current Assignee: Centre National De La Recherche Scientifique, Idenix Pharmaceuticals LLC (Merck & Co., Inc.)
• Original Assignee: Centre National De La Recherche Scientifique, Idenix Pharmaceuticals (Merck & Co., Inc.), Universite Montpellier II
• Inventors: Parsy, Christophe Claude, Alexandre, Francois-Rene, Dousson, Cyril B., Gosselin, Gilles, Rahali, Houcine, Surleraux, Dominique, Dukhan, David
• Primary Examiner(s): Bland, Layla
• Application Number:
  US13/899,487
• Publication Number:
  US 20130315867A1
• Time in Patent Office: 1,043 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/11 containing cyclic phosphate
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/213 containing cyclic phosphate

Abstract

Provided herein are compounds, compositions and methods for the treatment of Flaviviridae infections, including HCV infections. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents.

Claims

1. A compound of Formula (VIII):

2. The compound of claim 1, wherein each Z is independently —

(C_1-10)alkylene-SC(O)(C_1-10)alkyleneC(O)O [(C_1-10)alkylene]_pC(R)₃, —

(C_1-10)alkylene-SC(O)(C_1-10)alkyleneN(R)C(O)O [(C_1-10)alkylene]_pC(R)₃, —

(C(R)₂)_mC(O)O(C(R)₂)_nC(R)₃, —

(C(R)₂)_mArC(O)O(C(R)₂)_nC(R)₃, —

C(R)(E)(C(R)₂)_nOC(O)O(C(R)₂)_nC(R)₃, —

(C(R)₂)_mSC(O)(C(R)₂)_mOH, —

(C(R)₂)_mSC(O)(C(R)₂)_mOC(O)(C(R)₂)—

C(R)₃, —

(C(R)₂)_mS—

S(C(R)₂)_nC(R)₃, —

(C(R)₂)_mS—

S(C(R)₂)_mOH, —

(C(R)₂)_mN(R)C(O)O(C(R)₂)—

C(R)₃,

3. The compound of claim 1, wherein:

each B is independently C(R)₃(C(R)₂)_nOC(O)C(R)(B—

)N(R)C(O)O(C(R)₂)_nC(R)₃;

where B—

denotes the attachment position to Ar or L; and

each n is independently an integer selected over the range of 0 to 10.

4. The compound of claim 1, wherein each E is independently C₁-C₁₀ alkyl, C₅-C₁₀ aryl, or C₅-C₁₀ heteroaryl.

5. The compound of claim 1, wherein each Ar is independently C₅-C₁₀ arylene or C₅-C₁₀ heteroarylene.

6. The compound of claim 1, wherein each R is independently hydrogen, C₁-C₁₀ alkyl, C₅-C₁₀ aryl, or C₅-C₁₀ heteroaryl.

7. The compound of claim 1, wherein each R^A is independently a 3-20 membered carbocyclic or heterocyclic ring.

8. The compound of claim 1 wherein Y is fluoro.

9. The compound of claim 1 wherein Y is acetoxyl.

10. The compound of claim 1 wherein Y is hydroxyl.

11. The compound of claim 1 according to Formula (IX):

12. The compound of claim 11, wherein each Z is independently -LSC(O)LC(O)O(L)_pC(R)₃ or -LSC(O)LN(R)C(O)O(L)_pC(R)₃.

13. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient, carrier or diluent.

14. The pharmaceutical composition of claim 13, wherein the composition is an oral formulation.

15. A method for the treatment of a host infected with a hepatitis C virus, comprising the administration of an effective treatment amount of a compound or composition of claim 1.

16. The method of claim 15, wherein the host is a human.

17. The method of claim 15, wherein the administration directs a substantial amount of the compound or pharmaceutically acceptable salt thereof, to a liver of the host.

18. The method of claim 15, wherein the compound or composition is administered in combination or alternation with a second anti-viral agent selected from the group consisting of an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a non-nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin inhibitor, and combinations thereof.

19. A compound of Formula (VIII):

20. The compound of claim 19, wherein each straight-chained or branched C_1-10 unsubstituted alkylene is independently methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, t-butylene, pentylene, isopentylene, neopentylene, hexylene, isohexylene, 3-methylpentylene, 2,2-dimethylbutylene, or 2,3-dimethylbutylene.

21. The compound of claim 19, wherein

each X is alkoxyl of formula —

OR′

, wherein R′

is C_1-10 alkyl or C_3-15 cycloalkyl;

each E is independently C_1-10 unsubstituted alkyl, C_1-10 substituted alkyl, aryl, or heteroaryl;

each Ar is independently C₅-C₁₀ arylene or C₅-C₁₀ heteroarylene;

each L is independently C₁-C₁₀ substituted alkylene;

each R is independently C_1-10 unsubstituted alkyl, C_1-10 substituted alkyl, aryl, or heteroaryl;

wherein

each C_1-10 substituted alkyl is independently C_1-10 alkyl substituted by a moiety which is halogen, fluoro, chloro, bromo, iodo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

each C_1-10 substituted alkylene is independently C_1-10 alkylene substituted by a moiety which is halogen, fluoro, chloro, bromo, iodo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

each aryl is independently phenyl, biphenyl, and naphthyl, unsubstituted or substituted by a moiety which is halogen fluoro, chloro, bromo, iodo, alkyl, haloalkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate;

each heteroaryl is independently furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, thienopyridyl, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, or xanthenyl.